HCV represents a major global public health problem, infecting approximately 70 million people worldwide. There is currently no approved vaccine to counter HCV infection, and it is estimated that there are more than 40,000 new infections annually in the US alone with an additional 3-4 million new infections per year in the rest of world (Center for Disease Control). Chronic HCV infection is curable by an effective, albeit expensive, antiviral therapy ($50,000/treated patient). Drug treatment is not, however, a feasible route to worldwide eradication of HCV infection, as the cost of doing so would prohibitive. Moreover, successful treatment of a patient infected with one viral genotype does not preclude re-infection with another. The drug treatment approach is also complicated by the fact that most affected individuals are unaware that they are infected, and many engage in risky behaviors, such as intravenous drug use. Simply put, the best long term solution is to invest considerable intellectual and financial resources in discovery and development of a polyvalent vaccine effective against most, if not all, HCV viral genotypes. HCVs virion is a structurally heterogeneous particle which harbors a buoyant density lower than that of most other viruses, making it unique among known viruses. The virion associates with several host derived apolipoproteins and two surface glycoproteins, E1 and E2. E2 is responsible for cell targeting by interacting with the cellular receptors CD81 and scavenger receptor class B, type I (SR-BI). The function of E1 remains poorly understood. We and others published that the E2 core structure has a novel domain organization, lacks the hallmarks of a typical fusion peptide, and does not undergo large conformational or oligomeric changes upon exposure to low pH. As a result, E2 does not appear to have a direct role in membrane fusion, implying that E1 alone or the E1E2 heterodimer is responsible for the fusion process. These comprehensive structural, biochemical, and biophysical results have established a foundation to better define the functional roles of the envelope glycoproteins in HCV infection. Conserved viral epitopes on the surface of HCV can be made considerably more accessible to the immune system by deletion or modifying the immune evasion mechanism present on the virus. Working with an international group of investigators we deleted the hypervariable region 1 and selected glycosylation sites on the surface of E2, which have been shown to interfere with binding of several neutralizing antibodies (Khera et al. J Hepatol 2019). Interestingly, recombinant E2 proteins carrying these mutations are unable to elicit cross-neutralizing antibodies, suggesting that exposure of conserved epitopes is not sufficient to focus antibody responses on production of cross-neutralizing antibodies. The results of this study highlights highlights deficiencies in our understanding of HCV entry and neutralization, providing the impetus for continued research on HCV entry.